Development of CXCR4 modulators based on the lead compound RB-108

Abstract

The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds Ilb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.

Synthetically Feasible De Novo Molecular Design of Leads Based on a Reinforcement Learning Model: AI-Assisted Discovery of an Anti-IBD Lead Targeting CXCR4

“…To efficiently and expeditiously screen the binding affinity of compounds for CXCR4, our research group and collaborative teams have developed a competitive analysis method. ,− This method has been applied successfully for numerous years and has identified many potent CXCR4 antagonists, including a phase II clinical anti-inflammatory drug candidate Q-122. ,− These findings underscore the practicality of our method and its proficiency in accurately assessing the binding capability of test compounds to CXCR4. Therefore, based on our previous research, we used biotinylated TN14003 as a competitive CXCR4 antagonist and plerixafor (AMD3100) as a positive control on MDA-MB-231 cells.…”

Bisamide CXCR4 Modulators: Novel Anti‐IBD Agents Acting on the Chemotaxis of Inflammatory Cells

“…To evaluate whether the synthesized compounds can block the CXCR4/CXCL12 pathway, we first evaluated the competitive binding inhibitory rate of each compound to CXCR4 at the concentration of 10 × 10 −9 m . [ 4,14 ] The biotinylated TN14003, a potent CXCR4 antagonist, was used in this competitive binding experiment so as to effectively avoid the use of radioisotopes. Therefore, this in vitro model is more convenient and efficient for preliminary CXCR4 modulator activity screening.…”

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment

“…Instead of a traditional receptor built over the rhodopsin model by Palcewski et al ( 38 – 40 ), the human CXCR4 crystal structure (RCSB Protein Data Bank ID code 4RWS) published by Wu et al was adopted for this study ( 24 ). Most historical CXCR4 blockers are designed to contain multiple N-atoms owing to mimicking the highly positively charged nature ligand CXCL12 ( 23 , 41 – 49 ). Based on computer modeling studies, the most stable ligand–receptor complexes I, II, and III for three test compounds are individually generated through a docking-simulation algorithm as detailed in SI Appendix , Figs.…”